It is well-known that chemotherapy and radiotherapy can be neurotoxic, producing neural damage that can result in neuropathies and/or cognitive impairments. A significant subset of cancer survivors report ongoing cognitive problems after treatment, highlighting difficulties with memory, working memory and attention [2]. The consequent impact on daily function, return to work and quality of life has been described as the most troublesome survivorship issue that patients face [3]. Such chemotherapy-induced cognitive impairments (CICI) have been verified in several ways. First, objective neuropsychological testing indicates impairment in processing speed, attention/concentration, executive function, and verbal and visual memory in 17-50% of survivors, which persist for years post-treatment [4]. Second, neuroimaging studies of cancer survivors have correlated impaired performance in memory and executive function tasks with alterations in brain morphology and activation patterns in areas important for these tasks, such as the hippocampus and pre-frontal cortices [5, 6], and with extensive white matter abnormalities associated with cognitive impairment [7].
Further evidence shows that chemotherapy and radiotherapy have neurotoxic side-effects. Many patients develop painful and disabling neuropathies during chemotherapy, especially those receiving taxanes, such as docetaxel, and platinum compounds, such as oxaliplatin. Estimates vary, with between 70-90% of patients experiencing chemotherapy-induced peripheral neuropathies (CIPN) during treatment [8]. CIPN can present as a progressive and enduring tingling numbness, intense pain and hypersensitivity to cold and touch, beginning in the hands and feet and sometimes involving the arms and legs. CIPN is a significant source of distress during treatment, and can be the rate-limiting factor in treatment leading to either dose reduction or, in rare cases, cessation of chemotherapy. These effects are lasting. At 6 months after treatment, 30% of patients continue to experience CIPN [8] and are irreversible in 10-20% of patients [9]. CIPN has clear severe negative effects on patients' quality of life, sleep and mood after treatment [9].
Importantly, impairments in cognitive testing can occur in the absence of changes in locomotor activity, or anxiety, anhedonia or depressive-like behaviours [16]. Moreover, the cognitive impairments persist longer than allodynia in laboratory rats, indicating that poor performance in cognitive testing is not related to disability associated with pain [11].
Chemotherapy can lead to inactivity, malaise and lethargy, which can contribute to a downward spiral in health. Interventions that increase voluntary activity could alleviate this, and improve physical, neurological and mental health of cancer survivors.
Chemotherapy can lead to depression, anxiety, circadian rhythm disorders including impaired sleep, mental health issues, neuropsychiatric and neuropsychological disorders, which can impair quality of life for cancer survivors.
NAD+ levels decline with age [17], and are raised by calorie restriction and exercise in humans and in rodents. Interventions that raise NAD+ (e.g., calorie restriction and exercise) have been shown to reduce cancer risk and prevent tumor growth [19, 20], and reduce CIPN and CICI [42].
The NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) have been shown to improve metabolism and reverse aspects of ageing in elderly mice [17].
Axon degeneration occurs frequently in neurodegenerative diseases and peripheral neuropathies. The degeneration of transected axons is delayed in Wallerian degeneration slow (Wlds) mice with the overexpression of a fusion protein with the nicotinamide adenine dinucleotide (NAD+) synthetic enzyme, nicotinamide mononucleotide adenylyltransferase (Nmnat1). Both Wld(s) and Nmnat1 themselves are functional in preventing axon degeneration in neuronal cultures.
NAD+ levels decrease in injured, diseased, or degenerating neural cells (Araki et al Science 2004).
In summary, anti-cancer treatment with chemotherapy and/or radiotherapy has delivered increased survival rates for many cancers, at the cost of severe side effects that have a meaningful impact on survivor quality of life, which in the case of CIPN and cognitive impairment impact the feasibility of ongoing treatment. Thus, there is a need for new therapeutic strategies to treat or prevent chemotherapy and/or radiotherapy induced cognitive impairment and/or neuropathies.
Neuronal injury or impairment can have a variety of causes.
Neuronal injury can cause cognitive deficits such as decreased memory, slower processing speed, decreased concentration/attention, impaired spatial, verbal and visual memory, impaired executive function, impaired social interactions, impaired verbal and non-verbal communication, and impaired social interaction.
Neuronal injury can further cause mental health disorders such as depression, anxiety, risk of self harm and suicide, substance addiction and abuse.